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12 Penile Cancer - LR PDF
12 Penile Cancer - LR PDF
Penile Cancer
O.W. Hakenberg (chair), E. Compérat, S. Minhas,
A. Necchi, C. Protzel, N. Watkin
2. METHODOLOGY 4
2.1 References 5
4. EPIDEMIOLOGY 5
4.1 References 6
8. TREATMENT 17
8.1 Treatment of the primary tumour 17
8.1.1 Treatment of superficial non-invasive disease (CIS) 18
8.1.2 Treatment of invasive disease confined to the glans (category Ta/T1a) 18
8.1.2.1 Results of different surgical organ-preserving treatment modalities 18
8.1.2.2 Summary of results of surgical techniques 19
8.1.2.3 Results of radiotherapy for T1 and T2 disease 19
8.1.3 Treatment of invasive disease confined to the corpus spongiosum/glans
(Category T2) 20
8.1.4 Treatment of disease invading the corpora cavernosa and/or urethra
(category T2/T3) 20
8.1.5 Treatment of locally advanced disease invading adjacent structures
(category T3/T4) 20
8.1.6 Local recurrence after organ-conserving surgery 20
8.1.7 Recommendations for stage-dependent local treatment of penile carcinoma. 21
8.1.8 References 21
8.2 Management of regional lymph nodes 24
8.2.1 Management of patients with clinically normal inguinal lymph nodes (cN0) 24
8.2.1.1 Surveillance 24
8.2.1.2 Invasive nodal staging 24
8.2.2 Management of patients with palpable inguinal nodes (cN1/cN2) 25
8.2.2.1 Radical inguinal lymphadenectomy 25
8.2.2.2 Pelvic lymphadenectomy 25
8.2.2.3 Adjuvant treatment 26
8.2.3 Management of patients with fixed inguinal nodes (cN3) 26
8.2.4 Management of lymph node recurrence 26
8.2.5 The role of radiotherapy for the treatment of lymph node disease 26
8.2.6 Recommendations for treatment strategies for nodal metastases 27
8.2.7 References 27
9. FOLLOW-UP 33
9.1 When and how to follow-up 33
9.2 Recurrence of the primary tumour 34
9.3 Regional recurrence 34
9.4 Recommendations for follow-up in penile cancer 34
9.5 References 35
2. METHODOLOGY
A systematic literature search on penile cancer was performed by all members of the EAU Penile Cancer
Working Group covering the period between August 2008 and November 2013. At the onset of the project,
the relevant literature databases were searched. All titles relating to penile cancer (n = 1,602) were reviewed
by two panel members (OWH and CP). After exclusion of case reports, many reviews and irrelevant papers as
well as non-English language literature, the remaining papers were reviewed by abstract (n = 582). After further
exclusion of irrelevant literature, the remaining papers (n = 352) were retrieved and reviewed. This literature
was discussed at a panel meeting and necessary changes to the guideline were agreed. Other national and
international guideline documents on penile cancer were reviewed as well (National Comprehensive Cancer
Network (4), French Association of Urology (5) and the European Society of Medical Oncology (6). A draft
for discussion was circulated among all panel members several times December 2013, reviewed and finally
agreed.
References used in the text have been assessed according to their level of scientific evidence (table 1), and
guideline recommendations have been graded (table 2) according to the Oxford Centre for Evidence-based
Medicine Levels of Evidence (7). The aim of grading recommendations is to provide transparency between
the underlying evidence and the recommendation given. Due to the relative rarity of penile cancer, there is a
uniform lack of large series and randomized controlled trials. As a result of this, the levels of evidence (LE) and
grades of recommendation (GR) provided in the document are by necessity relatively low compared to those in
guidelines concerning more common diseases. All texts can be viewed and downloaded for personal use at the
society website: http://www.uroweb.org/guidelines/online-guidelines/.
Type of evidence LE
Evidence obtained from meta-analysis of randomised trials 1a
Evidence obtained from at least one randomised trial 1b
Evidence obtained from one well-designed controlled study without randomisation 2a
Evidence obtained from at least one other type of well-designed quasi-experimental study 2b
Evidence obtained from well-designed non-experimental studies, such as comparative studies, 3
correlation studies and case reports.
Evidence obtained from expert committee reports or opinions or clinical experience of respected 4
Authorities
*Modified from (7).
Nature of recommendations GR
Based on clinical studies of good quality and consistency addressing the specific recommendations A
and including at least one randomised trial
Based on well-conducted clinical studies, but without randomised clinical trials B
Made despite the absence of directly applicable clinical studies of good quality C
*Modified from (7).
2.1 References
1. Solsona E, Algaba F, Horenblas S, et al; European Association of Urology. EAU Guidelines on Penile
Cancer. Eur Urol 2004 Jul;46(1):1-8.
http://www.ncbi.nlm.nih.gov/pubmed/15183542
2. Algaba F, Horenblas S, Pizzocaro-Luigi Piva G, et al; European Association of Urology. EAU guidelines
on penile cancer. Eur Urol 2002 Sep;42(3):199-203.
http://www.ncbi.nlm.nih.gov/pubmed/12234502
3. Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol 2010
Jun;57(6):1002-12.
http://www.ncbi.nlm.nih.gov/pubmed/20163910
4. Clark PE, Spiess PE, Agarwal N, et al; National Comprehensive Cancer Network. Penile cancer:
Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2013 May;11(5):594-615.
http://www.ncbi.nlm.nih.gov/pubmed/23667209
5. Souillac I, Avances C, Camparo P, et al. Penile cancer in 2010: update from the Oncology Committee
of the French Association of Urology: external genital organs group (CCAFU-OGE). Prog Urol 2011
Dec;21(13):909-16.
http://www.ncbi.nlm.nih.gov/pubmed/22118355
6. Van Poppel H, Watkin NA, Osanto S, et al; ESMO Guidelines Working Group. Penile cancer: ESMO
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 Oct;24 Suppl
6:vi115-24.
http://www.ncbi.nlm.nih.gov/pubmed/23975666
7. Oxford Centre for Evidence-based Medicine Levels of Evidence. Produced by Bob Phillips, Chris Ball,
Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.
Updated by Jeremy Howick March 2009.
http://www.cebm.net/index.aspx?o=1025 [Access date January 2014]
4. EPIDEMIOLOGY
In Western countries, primary penile cancer is uncommon, with an incidence of less than 1.00 per 100,000
males in Europe and the United States (1,2). However, there are significant geographical variations within
Europe (Figure 1) reporting an incidence greater than 1.00 per 100,000 men (3). Incidence is also affected by
race and ethnicity in North America (1), with the highest incidence of penile cancer found in white Hispanics
(1.01 per 100,000), followed by a lower incidence in Alaskan, Native American Indians (0.77 per 100,000),
blacks (0.62 per 100,000) and white non-Hispanics (0.51 per 100,000), respectively. In contrast, in some other
parts of the world such as South America, South East Asia and parts of Africa the incidence of penile cancer
is much higher and can represent 1-2% (3) of malignant diseases in men. Penile cancer is common in regions
with a high prevalence of human papilloma virus (HPV) (1). The annual age-adjusted incidence is 0.7-3.0 per
Spain, Albacete
Malta
Switzerland, Neuchatel
France, Haut-Rhin
Italy, Ragusa Province
UK, Scotland
Denmark
Austria, Tyrol
Norway
Spain, Asturias
France, Bas-Rhin
UK, England
Estonia
Slovakia
Switzerland, Ticino
The Netherlands
Belgium Flanders (excl. Limburg)
Italy, Torino
Poland, Warsaw city
Germany, Saarland
Portugal, Vila Nova de Gaia
Slovenia
Italy, Sassari
0 0.5 1.0 1.5 2.0
4.1 References
1. Backes DM, Kurman RJ, Pimenta JM, et al. Systematic review of human papillomavirus prevalence in
invasive penile cancer. Cancer Causes Control 2009 May;20(4):449-57.
http://www.ncbi.nlm.nih.gov/pubmed/19082746
2. Chaux A, Netto GJ, Rodríguez IM, et al. Epidemiologic profile, sexual history, pathologic features, and
human papillomavirus status of 103 patients with penile carcinoma. World J Urol 2013 Aug;31(4):
861-7.
http://www.ncbi.nlm.nih.gov/pubmed/22116602
3. Parkin DM, Whelan SL, Ferlay J, et al. Cancer Incidence in Five Continents. Vol. VIII. IARC Scientific
Publications. No. 155. Lyon, France: IARC, 2002
http://www.iarc.fr/en/Publications/PDFs-online/Cancer-Epidemiology
4. Parkin DM, Bray F. The burden of HPV-related cancers. Vaccine 2006 Aug;Suppl 3:S3/11-25.
http://www.ncbi.nlm.nih.gov/pubmed/16949997
Table 3: Recognized aetiological and epidemiological risk factors for the development of penile cancer
Human papilloma virus infection is an important risk factor for developing penile cancer. DNA of HPV has been
identified in 70-100% of intraepithelial neoplasia and in 30-40% of invasive penile cancer tissue samples (LE:
2a). The HPV virus plays an important role in oncogenesis through the interaction with oncogenes and tumour
suppressor genes (P53, Rb genes) (14).The rate of HPV-positivity differs between different histological subtypes
of penile cancer. This suggests that HPV is a cofactor in the carcinogenesis of some variants of penile SCC
while other variants of penile cancer are not related to HPV (7). This corresponds to the finding of a higher
incidence of penile cancer in regions with a high prevalence of HPV. HPV subtypes most commonly found
in penile cancer are types 16 and 18 (15). The risk of penile cancer is increased in patients with condyloma
acuminata (16) (LE: 2b).
It is not clear whether HPV-associated penile cancer differs in prognosis from non-HPV-associated
penile cancer. A significantly better 5-year disease-specific survival has been reported for HPV-positive versus
HPV-negative cases (93% vs 78%) in one study (17) while no difference in lymph node metastases and 10-year
survival rate was reported in another (18).
There is no association between the incidence of penile cancer and cervical cancer except through
the link with the prevalence of HPV infections (19,20). Female sexual partners of patients with penile cancer
do not have an increased incidence of cervical cancer. There is at present no recommendation for the use of
HPV vaccination in boys due to a different HPV-associated risk pattern in penile and anal cancer; furthermore,
the epidemiological effects of HPV vaccination and its acceptance in girls will have to be assessed before any
further recommendations can be made (21,22).
Phimosis is strongly associated with the development of invasive penile cancer (3,9,23,24), probably
due to associated chronic infection since smegma is not a carcinogen (23). A further risk factor suggested
by epidemiological studies is cigarette smoking, which is associated with a 4.5-fold increased risk (95%
CI: 2.0-10.1) (24). The incidence of lichen sclerosus (balanitis xerotica obliterans) in patients with penile cancer
5.1 References
1. Dillner J, von Krogh G, Horenblas S, et al. Etiology of squamous cell carcinoma of the penis. Scand J
Urol Nephrol Suppl 2000;(205):189-93.
http://www.ncbi.nlm.nih.gov/pubmed/11144896
2. Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical conditions, and sexual
activity and risk of penile cancer. J Natl Cancer Inst 1993 Jan;85(1):19-24.
http://www.ncbi.nlm.nih.gov/pubmed/8380060
3. Tsen HF, Morgenstern H, Mack T, et al. Risk factors for penile cancer: results of a population-based
case-control study in Los Angeles County (United States). Cancer Causes Control 2001 Apr;12(3):
267-77.
http://www.ncbi.nlm.nih.gov/pubmed/11405332
4. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoralen UV-A therapy and narrowband
UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol
2012 May;(26 Suppl 3):22-31.
http://www.ncbi.nlm.nih.gov/pubmed/22512677
5. Stern RS; PUVA Follow-Up Study. The risk of squamous cell and basal cell cancer associated with
psoralen and ultraviolet A therapy: a 30-year prospective study. J Am Acad Dermatol 2012;66(4):
553-62.
http://www.ncbi.nlm.nih.gov/pubmed/22264671
6. Daling JR, Sherman KJ, Hislop TG, et al. Cigarette smoking and the risk of anogenital cancer.
Am J Epidemiol 1992 Jan;135(2):180-9.
http://www.ncbi.nlm.nih.gov/pubmed/1311142
7. Stankiewicz E, Kudahetti SC, Prowse DM, et al. HPV infection and immunochemical detection of cell-
cycle markers in verrucous carcinoma of the penis. Mod Pathol 2009 Sep;22:1160-8.
http://www.ncbi.nlm.nih.gov/pubmed/19465901
8. Backes DM, Kurman RJ, Pimenta JM, et al. Systematic review of human papillomavirus prevalence in
invasive penile cancer. Cancer Causes Control 2009 May;20(4):449-57.
http://www.ncbi.nlm.nih.gov/pubmed/19082746
9. Koifman L, Vides AJ, Koifman N, et al. Epidemiological aspects of penile cancer in Rio de Janeiro:
evaluation of 230 cases. Int Braz J Urol 2011 Mar-Apr;37(2):231-40;discussion 240-3.
http://www.ncbi.nlm.nih.gov/pubmed/21557840
10. Thuret R, Sun M, Budaus L, et al. A population-based analysis of the effect of marital status on overall
and cancer-specific mortality in patients with squamous cell carcinoma of the penis. Cancer Causes
Control 2013 Jan;24(1):71-9.
http://www.ncbi.nlm.nih.gov/pubmed/23109172
11. McIntyre M, Weiss A, Wahlquist A, et al. Penile cancer: an analysis of socioeconomic factors at a
southeastern tertiary referral center. Can J Urol 2011 Feb;18(1):5524-8.
http://www.ncbi.nlm.nih.gov/pubmed/21333043
12. Benard VB, Johnson CJ, Thompson TD, et al. Examining the association between socioeconomic
status and potential human papillomavirus-associated cancers. Cancer 2008 Nov;113(10 Suppl):
2910-8.
http://www.ncbi.nlm.nih.gov/pubmed/18980274
13. Ulff-Møller CJ, Simonsen J, Frisch M. Marriage, cohabitation and incidence trends of invasive penile
squamous cell carcinoma in Denmark 1978-2010. Int J Cancer 2013 Sep;133(5):1173-9.
http://www.ncbi.nlm.nih.gov/pubmed/23404289
14. Kayes O, Ahmed HU, Arya M, et al. Molecular and genetic pathways in penile cancer. Lancet Oncol
2007 May;8(5):420-9.
http://www.ncbi.nlm.nih.gov/pubmed/17466899
Clinical classification
T - Primary Tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
Ta Non-invasive carcinoma
T1 Tumour invades subepithelial connective tissue
T1a umour invades subepithelial connective tissue without lymphovascular invasion and is not
T
poorly differentiated or undifferentiated (T1G1-2)
T1b Tumour invades subepithelial connective tissue with lymphovascular invasion or is poorly
differentiated or undifferentiated (T1G3-4)
T2 Tumour invades corpus spongiosum and/or corpora cavernosa
T3 Tumour invades urethra
T4 Tumour invades other adjacent structures
N - Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
N0 No palpable or visibly enlarged inguinal lymph node
N1 Palpable mobile unilateral inguinal lymph node
N2 Palpable mobile multiple unilateral or bilateral inguinal lymph nodes
N3 Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral
M - Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
Pathological classification
The pT categories correspond to the clinical T categories. The pN categories are based upon biopsy or
surgical excision.
pN - Regional Lymph Nodes
pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Intranodal metastasis in a single inguinal lymph node
pN2 Metastasis in multiple or bilateral inguinal lymph nodes
pN3 etastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of any regional
M
lymph node metastasis
pM - Distant Metastasis
pM0 No distant metastasis
pM1 Distant metastasis
G - Histopathological Grading
GX Grade of differentiation cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3-4 Poorly differentiated/undifferentiated
6.2 Pathology
Squamous cell carcinoma accounts for more than 95% of cases of malignant diseases of the penis. It is not
known how often SCC is preceded by premalignant lesions (Table 5) (4-7). Although SCC is the most common
penile neoplasia, distinct different histological types with varying growth patterns, clinical aggressiveness and
HPV association have been identified (8-10) (tables 5 and 6).
Some variants of primary penile cancer that have been described have so far not been included in
the WHO classification (pseudohyperplastic carcinoma, carcinoma cuniculatum, pseudoglandular carcinoma,
warty-basaloid carcinoma).
Gross handling
Tissue sections determine the accuracy of histological diagnosis. Small lesions should be totally included,
bigger lesions should have at least 3-4 blocks. Lymph nodes have to be totally included in order to be sure to
detect micro-metastases. Surgical margins have to be completely included.
Pathology report
This has to include the anatomical site of the primary tumour, the histological type/subtypes, grade, perineural
invasion, depth of invasion, vascular invasion (venous/lymphatic), irregular growth and front of invasion, urethral
invasion, invasion of corpus spongiosum/cavernosum and surgical margins.
The classification of invasion of the corpus spongiosum and the corpora cavernosa into the same pT2 group
is clinically problematic as these signify a very different prognosis. Rees et al. (2) reported 72 patients with pT2
tumours; local recurrence (35% vs. 17%) and mortality (30% vs. 21%) rates were higher in patients with tunica
or cavernosal involvement versus glans-only invasion after a mean follow-up of 3 years (LE: 2b). The authors
proposed defining T2a with spongiosum-only invasion and T2b with tunica or corpus cavernosum invasion.
A retrospective analysis of the records of 513 patients treated between 1956 and 2006 also reported this
prognostic difference (3).
Long-term survival in patients with T2 and T3 tumours and in patients with N1 and N2 disease (in the
1987-2002 TNM classification) does not seem to differ significantly (3) (LE: 2a).
Two nomograms which can be used to estimate prognosis in penile cancer have been developed but as usual
in penile cancer are based on small numbers. Solsona et al. in a prospective validation of their nomogram
suggested that pT1G1 tumours are low risk tumours regarding cancer-specific mortality, while pT2/3 G2/3
are high-risk tumours, with the others being intermediate risk. Lymph node metastases were observed in 0%,
33% and 83% of low-, intermediate- and high-risk cases, respectively (18). Similar findings were reported
by Hungerhuber et al. who recommend prophylactic lymphadenectomy for high risk patients (19). Chaux et
al. proposed a “prognostic index” based on findings in 193 patients which incorporates several pathological
parameters such as grade, deepest anatomical level, perineural invasion and permits scoring in a ranking
system which can be used to predict the likelihood of inguinal lymph node metastases and the likelihood of
5-year survival (20). Low scores confer a 95% chance of 5-year survival, intermediate scores a 65% and high
scores a 45%.
Molecular biology
There are so far few data which link chromosomal abnormalities in penile SCC to biological behaviour and
patient outcome (21). DNA copy number alterations found in penile carcinoma are comparable to those
found in SCC of other origins. Lower copy numbers and alteration numbers in penile SCC have been linked
to poorer survival. Alterations in the locus 8q24 seem to play a major role and have also been implicated
in the carcinogenesis of other neoplasms such as prostate cancer (22,23). Telomerase activity has been
Penile biopsy
Often the diagnosis of penile cancer is without clinical doubt but in rare cases non-SCC penile carcinoma or
inflammatory lesions may be misleading. Therefore, histological verification by biopsy should be mandatory
before any local treatment is undertaken.
In cases, where definitive surgical treatment is planned, confirmatory frozen section excisional biopsy
can be done before continuing with the ablative surgical procedure. In all cases where the diagnosis is clinically
uncertain and/or when non-surgical treatment is planned, histological verification must be obtained before
treatment.
In the management of penile cancer there is need for histological confirmation if:
• there is doubt about the exact nature of the lesion (e.g. CIS, metastasis or melanoma) and/or;
• treatment with topical agents, radiotherapy or laser surgery is planned;
• treatment of the lymph nodes is based on preoperative histological information (risk-adapted strategy).
When performing a biopsy, the size of the biopsy is important. Studies of biopsies with an average size of
0.1 cm found that there was difficulty in evaluating the extent of depth of invasion in 91% of biopsies, there
was discordance between the grade at biopsy and in the final specimen in 30% of cases and that there was
failure to detect cancer in 3.5% of cases (4). Also, vascular and lymphatic tumour emboli were detected in only
9-11% of cases. Thus, although a punch biopsy may be sufficient for superficial lesions, an excisional biopsy is
preferable which should be deep enough to assess the degree of invasion and stage adequately.
6.2.1 References
1. Sobin LH, Gospodariwics M, Wittekind C (eds). TNM Classification of Malignant Tumours. UICC
International Union Against Cancer 7th edition, Willy-Blackwell, 2009 Dec; 239-42.
http://www.uicc.org/tnm/
2. Rees RW, Freeman A, Borley N, et al. pT2 penile squamous cell carcinomas: cavernosus vs.
spongiosus invasion. Eur Urol Suppl 2008;7(3):111 (abstract #163).
http://www.europeanurology.com/article/S1569-9056(08)60162-1/fulltext
3. Leijte JA, Gallee M, Antonini N, et al. Evaluation of current (2002) TNM classification of penile
carcinoma. J Urol 2008;180(3):933-8;discussion 938.
http://www.ncbi.nlm.nih.gov/pubmed/18635216
4. Velazquez EF, Barreto JE, Rodriguez I, et al. Limitations in the interpretation of biopsies in patients with
penile squamous cell carcinoma. Int J Surg Pathol 2004 Apr;12(2):139-46.
http://www.ncbi.nlm.nih.gov/pubmed/15173919
5. Velazquez EF, Cubilla AL. Lichen sclerosus in 68 patients with squamous cell carcinoma of the penis:
frequent atypias and correlation with special carcinoma variants suggests a precancerous role. Am
Surg Pathol 2003 Nov;27:1448-53.
http://www.ncbi.nlm.nih.gov/pubmed/14576478
6. Teichman JM, Thompson IM, Elston DM. Non infectious penile lesions. Am Fam Physician 2010
Jan;81(2):167-74.
http://www.ncbi.nlm.nih.gov/pubmed/20082512
GR
Primary tumour
Physical examination, recording morphology, extent and invasion of penile structures. C
MRI with artificial erection in selected cases with intended organ preserving surgery.
Inguinal lymph nodes
Physical examination of both groins, recording number, laterality and characteristics of inguinal nodes C
• If nodes are not palpable, invasive lymph node staging in high-risk patients (see section 8).
• If nodes are palpable, a pelvic CT may be indicated, PET/CT is an option.
Distant metastases
In N+ patients, abdomino-pelvic CT scan and chest X-ray are required for systemic staging. PET/CT C
scan is an option.
In patients with systemic disease or with relevant symptoms, a bone scan may be indicated.
CT = computed tomography; PET = positron emission tomography.
7.5 References
1. Bertolotto M, Serafini G, Dogliotti L, et al. Primary and secondary malignancies of the penis:
ultrasound features. Abdom imaging 2005 Jan-Feb;30(1):108-12.
http://www.ncbi.nlm.nih.gov/pubmed/15759326
2. Lont AP, Besnard AP, Gallee MP, et al. A comparison of physical examination and imaging in
determining the extent of primary penile carcinoma. BJU Int 2003 Apr;91(6):493-5.
http://www.ncbi.nlm.nih.gov/pubmed/12656901
3. Kayes O, Minhas S, Allen C, et al. The role of magnetic resonance imaging in the local staging of
penile cancer. Eur Urol 2007 May; 51(5):1313-8;discussion 1318-9.
http://www.ncbi.nlm.nih.gov/pubmed/17113213
4. Petralia G, Villa G, Scardino E, et al. Local staging of penile cancer using magnetic resonance imaging
with pharmacologically induced penile erection. Radiol Med 2008 Jun;113(4):517-28.
http://www.ncbi.nlm.nih.gov/pubmed/18478188
5. Krishna RP, Sistla SC, Smile R, et al. Sonography: an underutilized diagnostic tool in the assessment
of metastatic groin nodes. J Clin Ultrasound 2008 May;36(4):212-7.
http://www.ncbi.nlm.nih.gov/pubmed/17960822
6. Mueller-Lisse UG, Scher B, Scherr MK, et al. Functional imaging in penile cancer: PET/computed
tomography, MRI, and sentinel lymph node biopsy. Curr Opin Urol 2008 Jan;18(1):105-10.
http://www.ncbi.nlm.nih.gov/pubmed/18090498
8. TREATMENT
8.1 Treatment of the primary tumour
The aims of the treatment of the primary penile cancer lesion are complete tumour removal with as much organ
preservation as possible while radicality of the treatment should not be compromised. A local recurrence in
itself has little influence on long-term survival so that organ preservation strategies are justified (1).
There are no randomised controlled trials for any of the surgical management options of localised
penile cancer, neither are there any observational studies comparing different surgical approaches or studies
comparing surgical and non-surgical treatment modalities. The available studies all have one or more form of
bias such as bias of selection, performance, detection, attrition, selective reporting or publication. Thus, the
overall quality of the existing evidence must be regarded as low.
Penile preservation appears to be superior in functional and cosmetic outcomes and should be offered as the
primary treatment modality to men with localised penile cancer. However, there are no randomized studies
comparing organ-preserving and ablative treatment strategies. There are only retrospective studies with a level
of evidence of 3 or less.
Histological diagnosis with local staging must be obtained in all cases, especially if non-surgical
treatment modalities are considered (GR: C).
For all surgical treatment options, the intra-operative assessment of surgical margins by frozen section is
recommended (GR: C) as tumour-positive margins lead to local recurrence (5). Total removal of the glans
(glansectomy) and prepuce does have the lowest recurrence rate among the treatment modalities for small
penile lesions (2%) (5). Negative surgical margins are imperative when using penile-conserving treatments (GR:
C) and a margin of 5 mm is considered oncologically safe (5,6).
Treatment choice should depend on tumour size, histology including stage and grade, localization
especially relative to the meatus, as well as patient preference as there are no documented differences in the
long term local recurrence rates between surgery, laser and radiation therapy.
Laser therapy
Laser ablation can be done with a Nd:YAG laser or a CO2 laser (7-12), visualisation may be improved by
photodynamic diagnosis.
The results of CO2 laser treatment have been reported by three studies all from the same institution
(7-9). Laser treatment was given in combination with radio- or chemotherapy and patients included had CIS
or T1 penile cancers. Follow-up was 5 years (median) in all three studies. There is some overlap between the
cohorts reported, in total 195 patients are included in these retrospective series.
No cancer-specific deaths were reported in any of these three studies. In one, an estimated cumulative
risk of local recurrence at five years was given with 10% (106 patients with CIS) and 16% (78 patients with T1
tumour) (7). In all three series taken together, local recurrence ranged from 14% for CIS and T1 tumours (9) to
23% (T1 tumours) (8). The reported rate of inguinal nodal recurrence after local CO2 laser treatment was 0%
(0/11) (9) and 4% (2/56) (8). Secondary partial penectomy at 10 years was 3% and 10%, depending on the
tumour (CIS vs T1) and whether combination treatment had been given or not (7).
The four studies on the results of Nd:YAG laser treatment (10-13) together report a total of 150
patients with a follow-up of at least 4 years. Local recurrence rates at last follow-up ranged across the four
studies from 10% (3/29) (10) to 48% (21/44) (11). In one of these studies (12), recurrence-free survival rates
were reported as 100%, 95% and 89% at one, two and five years. Inguinal nodal recurrence were reported
in 21% (9/44) (10). Cancer-related deaths were reported in 2% (1/54) (13) and 9% of patients (4/44) (11),
Glans resurfacing
Three studies have reported results of this technique (21-23) with a total of 71 patients with stages CIS or
T1. Shabbir et al. report results of total and partial glans resurfacing (23). The range of the median duration of
follow-up in the three studies was 21-30 months. No cancer-specific deaths were reported, the rates of local
recurrence were 0% (0/10) (21) and 6% (2/33) (22) without reports of nodal recurrence. There were no reported
complications in any of the three studies.
Glansectomy
Results of another fairly new technique, glansectomy, were reported by three studies (5,24,25), whereby Li et al.
also reports on glans-preserving surgery (25). A total of 68 patients with a follow-up of 114 months (24) and 63
months (25) were included. One patient (8%) had a local recurrence (24) and 6 patients (9%) had inguinal nodal
metastases. There were no cancer-specific deaths reported. Another group reported 87 patients with 6 local
(6.9%), 11 regional (12.6%) and 2 systemic recurrences (2.3%) during a mean follow-up of 42 months (5).
Partial penectomy
Results of partial penectomy were reported in eight rather heterogeneous studies (25-32) amounting to 184
included patients. Tumour stages included were T1-T3. Reported follow-up ranged from 40-194 months.
0-27% of patients were reported to have died of penile cancer, local recurrence rates ranged from 4-50% of
patients. The 5-year overall survival rate was reported by three studies and ranged from 59 to 89% (28,29,32).
Summary of treatment recommendations for non-invasive and localized superficially invasive penile
cancer
8.1.3 Treatment of invasive disease confined to the corpus spongiosum/glans (Category T2)
Total glansectomy, with or without resurfacing of the corporeal heads, is recommended (42) (LE: 3; GR: C).
Radiotherapy is an option (see below, section 8.1.7). Partial amputation should be considered in patients who
are unfit for reconstructive surgery (40) (GR: C).
8.1.4 Treatment of disease invading the corpora cavernosa and/or urethra (category T2/T3)
Partial amputation with a tumour-free margin with reconstruction is standard treatment (37) (GR: C). A surgical
margin of 5 mm is considered safe (5,6) but patients should remain under close follow-up. Radiotherapy is an
option.
8.1.5 Treatment of locally advanced disease invading adjacent structures (category T3/T4)
These are relatively rare (Europe 5%, Brazil 13%) (6). Total penectomy with perineal urethrostomy is standard
surgical treatment for T3 tumours (6) (GR: C).
In more advanced disease (T4) neoadjuvant chemotherapy may be advisable, followed by surgery
in responders as in the treatment of patients with fixed enlarged inguinal nodes (see section 8.2.4) (GR: C).
Otherwise, adjuvant chemotherapy or palliative radiotherapy may be an option (GR: C; see sections 8.2.4 and
8.1.7).
8.1.8 References
1. Leijte JA, Kirrander P, Antonini N, et al. Recurrence patterns of squamous cell carcinoma of the
penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol 2008
Jul;54(1):161-8.
http://www.ncbi.nlm.nih.gov/pubmed/18440124
2. Alnajjar HM, Lam W, Bolgeri M, et al. Treatment of carcinoma in situ of the glans penis with topical
chemotherapy agents. Eur Urol 2012 Nov;62(5):923-8.
http://www.ncbi.nlm.nih.gov/pubmed/22421082
3. Paoly J, Ternesten Bratel A, Löwhagen GB, et al. Penile intraepithelial neoplasia: results of
photodynamic therapy. Acta Derm Venereal 2006;86(5):418-21.
http://www.ncbi.nlm.nih.gov/pubmed/16955186
4. Shabbir M, Muneer A, Kalsi J, et al. Glans resurfacing for the treatment of carcinoma in situ of the
penis: surgical technique and outcomes. Eur Urol 2011;59(1):142-7.
http://www.ncbi.nlm.nih.gov/pubmed/21050658
5. Philippou P, Shabbir M, Malone P, et al. Conservative surgery for squamous cell carcinoma of the
penis: resection margins and long-term oncological control. J Urol 2012 Sep;188(3):803-8.
http://www.ncbi.nlm.nih.gov/pubmed/22818137
6. Ornellas AA, Kinchin EW, Nóbrega BL, et al. Surgical treatment of invasive squamous cell carcinoma
of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol 2008;97(6):
487-95.
http://www.ncbi.nlm.nih.gov/pubmed/18425779
The management of regional lymph nodes is decisive for long-term patient survival. Cure can be achieved
in metastatic disease confined to the regional lymph nodes. Lymphadenectomy is the treatment of choice
for patients with inguinal lymph node metastases (GR: B) but multimodal treatment combining surgery and
polychemotherapy is often indicated.
Management of the regional lymph nodes should be stage-dependent. In clinically node-negative
patients (cN0), there is a definite risk of micro-metastatic lymph node involvement in about 25% of cases which
is related to local tumour stage and grade. In clinically positive lymph nodes (cN1/cN2), metastatic disease
is highly likely and no time should be wasted on antibiotic treatment before surgical treatment. With enlarged
fixed inguinal lymph nodes (cN3), multimodal treatment by chemotherapy and surgery is indicated. Capsular
penetration and extranodal extension in lymph node metastasis even if present in only one node carries a high
risk of progression and is classified as pN3 which also requires multimodal treatment.
8.2.1 Management of patients with clinically normal inguinal lymph nodes (cN0)
Risk stratification for the management of patients with clinically normal lymph nodes depends on stage, grade
and the presence or absence of lymphovascular invasion in the primary tumour (5). Tumours with low risk of
metastatic disease are those with superficial penile cancer (pTa, pTis) and low grade. pT1 tumours represent
a heterogeneous risk group: they can be considered low-risk if they are well differentiated (pT1G1), otherwise
they represent an intermediate-risk group (pT1G2) (6) or must be considered high risk (pT1G3) together with all
higher stages.
Several studies have shown that early inguinal lymphadenectomy in clinically node-negative patients
is far superior concerning long-term patient survival compared to therapeutic lymphadenectomy when regional
nodal recurrence occurs (7,8). One prospective study comparing bilateral lymphadenectomy, radiotherapy and
surveillance in clinically node-negative patients reported that 5-year overall survival was significantly better with
inguinal lymphadenectomy compared to immediate inguinal radiotherapy or that observed with a surveillance
strategy (74% vs 66% and 63%, respectively) (9).
8.2.1.1 Surveillance
Surveillance for the management of regional lymph nodes carries the risk of regional recurrence arising later
from existing micrometastatic disease. Patient survival is over 90% with early lymphadenectomy and below
40% with lymphadenectomy for regional recurrence later (10,11). This definite risk must be taken into account
when considering surveillance and the patient should be informed about this. Surveillance can only be
recommended in patients with pTis and pTa penile cancer, and with the appropriate caveats in pT1G1 tumours
(10,11,12). A prerequisite for surveillance is good patient information and compliance.
There are two invasive diagnostic procedures whose efficacy is evidence-based: modified inguinal
With both methods of invasive regional lymph node staging in cN0 patients, missing existing micro-metastatic
disease will lead to later regional recurrence with a dramatic deterioration in long-term survival (7). This false-
negative rate has been reported to be as high as 12-15% for the DSNB technique even in experienced centres
(11,12). The false-negative rate of mILND is not known. The risk of a false-negative result and its implications
for the prognosis should be explained to the patient before deciding on which method to use.
If lymph node metastasis is found with either method, an ipsilateral radical inguinal lymphadenectomy
is indicated.
8.2.5 The role of radiotherapy for the treatment of lymph node disease
The use of radiotherapy for nodal disease varies in different European countries and seems to follow tradition
and single institution policies rather than being evidence-based. Although radiotherapy is widely used in some
countries in the management of regional lymph node metastasis in penile cancer, there is hardly any published
evidence on its role.
Neither neoadjuvant nor adjuvant radiotherapy has been reported to improve oncological outcome
in node-positive penile cancer (43). One prospective trial comparing inguinal radiotherapy with inguinal node-
dissection reported superior results for surgery (9). Franks et al. reported poor long-term survival in patients
with adjuvant inguinal and pelvic radiotherapy (44). Adjuvant chemotherapy has been reported to be far
superior to adjuvant radiotherapy after radical inguinal lymphadenectomy in node-positive patients in one
retrospective series (38). In an analysis of the National Cancer Institute Surveillance, Epidemiology and End
8.2.7 References
1. Daseler EH, Anson BJ, Reimann AF. Radical excision of inguinal and iliac lymph glands: a study based
upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet
1948 Dec;87(6):679-94. [No abstract available]
http://www.ncbi.nlm.nih.gov/pubmed/18120502
2. Leijte JA, Valdés Olmos RA, Nieweg OE, et al. Anatomical mapping of lymphatic drainage in penile
carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection. Eur Urol 2008
Oct;54(4):885-90.
http://www.ncbi.nlm.nih.gov/pubmed/18120502
3. Riveros M, Garcia R, Cabanas R. Lymphadenography of the dorsal lymphatics of the penis. Technique
and results. Cancer 1967 Nov;20(11):2026-31.
http://www.ncbi.nlm.nih.gov/pubmed/6061637
4. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977 Feb;39(2):456-66.
http://www.ncbi.nlm.nih.gov/pubmed/837331
5. Graafland NM, Lam W, Leijte JA, et al. Prognostic factors for occult inguinal lymph node involvement
in penile carcinoma and assessment of the high-risk EAU subgroup: a two-institution analysis of 342
clinically node-negative patients. Eur Urol 2010 Nov;58(5):742-7.
http://www.ncbi.nlm.nih.gov/pubmed/20800339
6. Hughes BE, Leijte JAP, Kroon BK, et al. Lymph node metastasis in intermediate-risk penile squamous
cell cancer: a two-centre experience. Eur Urol 2010 Apr;57(4):688-92.
http://www.ncbi.nlm.nih.gov/pubmed/19647926
7. Leijte JA, Kirrander P, Antonini N, et al. Recurrence patterns of squamous cell carcinoma of the
penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol 2008
Jul;54(1):161-8.
http://www.ncbi.nlm.nih.gov/pubmed/18440124
8. Ornellas AA, Kinchin EW, Nóbrega BL, et al. Surgical treatment of invasive squamous cell carcinoma
of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol 2008 May;97(6):
487-95.
http://www.ncbi.nlm.nih.gov/pubmed/18425779
9. Kulkarni JN, Kamat MR. Prophylactic bilateral groin node dissection versus prophylactic radiotherapy
and surveillance in patients with N0 and N1-2A carcinoma of the penis. Eur Urol 1994;26(2):123-8.
http://www.ncbi.nlm.nih.gov/pubmed/7957466
8.3 Chemotherapy
8.3.1 Adjuvant chemotherapy in node-positive patients after radical inguinal lymphadenectomy
Multimodal treatment can improve patient outcome in many tumour entities. Adjuvant chemotherapy after
resection of nodal metastases in penile carcinoma has been reported in a few small and heterogeneous series
(1-5). Comparing different small scale clinical studies is fraught with difficulties.
The value of adjuvant chemotherapy after radical inguinal lymphadenectomy in node-positive penile
cancer was demonstrated by an Italian group who reported long-term disease-free survival (DFS) of 84% in
25 consecutive patients treated with 12 adjuvant weekly courses of vincristine, bleomycin, and methotrexate
(VBM) during the period 1979-1990 and compared this to a historical control group of 38 consecutive node-
positive patients with radical lymphadenectomy (with or without adjuvant inguinal radiotherapy) who had
achieved a DFS rate of only 39% (2).
This group has also published results of a chemotherapy regimen adjuvant to radical
lymphadenectomy in stage pN2-3 patients receiving three courses of cisplatin and 5-FU which they had been
using since 1991 with lower toxicity and even better results compared to VBM (4) (LE: 2b). The same group has
been using an adjuvant taxane-based regimen since 2004 (cisplatin, 5FU plus paclitaxel or docetaxel (TPF)) in
19 node-positive patients receiving 3-4 cycles of TPF after resection of pN2-3 disease (5). Of those patients,
52.6% were disease-free after a median follow up of 42 months and tolerability was good. Results of adjuvant
treatment with paclitaxel and cisplatin also improved outcome (6).
The use of adjuvant chemotherapy is recommended, in particular when the administration of the triple
combination chemotherapy is feasible, and curative treatment is aimed for (LE: 2b).
No data for the adjuvant chemotherapeutic treatment of penile carcinoma in stage pN1 are available.
The administration of an adjuvant treatment in pN1 disease is therefore recommended only in clinical trials.
Based on histological and other similarities of penile SCC with head & neck SCC, it may be assumed that
LE GR
Adjuvant chemotherapy (3-4 cycles of TPF) is an option for patients with pN2-3 tumours (5). 2b C
Neoadjuvant chemotherapy (4 cycles of a cisplatin and taxane-based regimen) followed by 2a B
radical surgery is recommended in patients with non-resectable or recurrent lymph node
metastases (5,14).
Chemotherapy for systemic disease is an option in patients with limited metastatic load. 3 C
TPF = cisplatin, 5FU plus paclitaxel or docetaxel.
9. FOLLOW-UP
Follow-up after curative treatment in penile carcinoma as in any malignant disease is important for two reasons:
• early detection of recurrence allows for potentially curative treatment. Local recurrence does not
significantly reduce long-term survival if successfully treated while inguinal nodal recurrence leads to a
drastic reduction in the probability of long-term disease-specific survival.
• the detection and management of treatment-related complications.
Local recurrence and regional nodal recurrence most frequently occur within two years of primary treatment.
The follow-up interval and strategies for patients with penile cancer are directed by the initial treatment of
the primary lesion and regional lymph nodes. In a multicentre study (1), during the first two years 74.3% of all
recurrences, 66.4% of local recurrences, 86.1% of regional recurrences and 100% of distant recurrences were
detected. In the same study, 92.2% of all recurrences occurred within the first 5 years and all recurrences seen
after 5 years were local recurrences or new primary lesions (1).
Therefore, an intensive follow-up regimen during the first 2 years is rational, with less intensive follow-
up needed thereafter for a minimum of 5 years. Generally, follow-up should continue thereafter but may be
omitted in well-educated and motivated patients who reliably continue to carry out regular self-examination (1).
10.4 References
1. Schover LR. Sexuality and fertility after cancer. Hematology Am Soc Hematol Educ Program
2005;523-7.
http://www.ncbi.nlm.nih.gov/pubmed/16304430
2. Skeppner E, Windahl T, Andersson S, et al. Treatment-seeking, aspects of sexual activity and life
satisfaction in men with laser-treated penile carcinoma. Eur Urol 2008 Sep;54(3):631-9.
http://www.ncbi.nlm.nih.gov/pubmed/18788122
3. Bandieramonte G, Colecchia M, Mariani L, et al. Peniscopically controlled CO2 laser excision for
conservative treatment of in situ and T1 penile carcinoma: report on 224 patients. Eur Urol 2008
Oct;54(4):875-82.
http://www.ncbi.nlm.nih.gov/pubmed/18243513
4. van Bezooijen BP, Horenblas S, Meinhardt W, et al. Laser therapy for carcinoma in situ of the penis.
J Urol 2001 Nov;166(5):1670-1.
http://www.ncbi.nlm.nih.gov/pubmed/11586199
5-FU 5-fluorouracil
BMP cisplatin, methotrexate and bleomycin
CT computed tomography
CSS cancer-specific survival
DFS disease-free survival
DSNB dynamic sentinel node biopsy
EAU European Association of Urology
FDA US Food and Drug Administration
FDG fluorodeoxyglucose
FNAB fine-needle aspiration biopsy
FNAC fine-needle aspiration cytology
GR grade of recommendation
HPV human papilloma virus
LAD lymphadenectomy
LE level of evidence
mILND modified inguinal lymphadenectomy
MRI magnetic resonance imaging
Nd:YAG neodynium:yttrium-aluminum-garnet
PET positron emission tomography
PF cisplatin and fluorouracil
QoL quality of life
SCC squamous cell carcinoma
SNB sentinel node biopsy
TC99m technetium 99m
TPF cisplatin, 5FU plus paclitaxel or docetaxel
TNM tumour, node, metastasis
VBM vinblastine, bleomycin, methotrexate
Conflict of interest
All members of the Penile Cancer Guidelines working group have provided disclosure statements on all
relationships that they have and that might be perceived to be a potential source of conflict of interest. This
information is kept on file in the European Association of Urology Central Office database. This guidelines
document was developed with the financial support of the European Association of Urology. No external
sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited
to administrative assistance as well as travel and meeting expenses. No honoraria or other reimbursements
have been provided.